DESCRIPTION (Applicant's abstract) The lipodystrophy syndrome is a newly recognized complication of HIV disease, which affects up to half of all HIV-infected patients on potent antiretroviral therapy, and for which there is no effective therapy. The syndrome is characterized primarily by fat redistribution, including truncal obesity, as well as peripheral fat loss. Although the mechanism of the syndrome is unknown, and may relate in part to protease inhibitor therapy, preliminary data suggest that the syndrome is characterized by fasting hyperinsulinemia. However, detailed evaluation of insulin dynamics in affected patients has not previously been performed, and it is unknown whether the syndrome is characterized by insulin resistance per se. If insulin resistance is shown, it is not known whether the defect is central, due to central hepatic insulin resistance and excessive glucose production or peripheral, related to diminished glucose utilization. This determination is critical for the establishment of appropriate therapy for insulin resistance in this population. One hypothesis in this proposal is that significant insulin resistance exists in the HIV-Iipodystrophy syndrome and is closely associated with visceral abdominal fat and increased fatty acid production in such patients. Furthermore, truncal adiposity and increased free fatty acid (FFA) production is hypothesized to result in primarily hepatic insulin resistance, compared to peripheral resistance. To investigate these hypotheses, insulin dynamics and visceral adiposity will be compared in both HIV-infected patients with and without lipodystrophy and healthy controls. Acute intervention with acipimox will be investigated to determine the role of FFA in the insulin resistance, and euglycemic clamp will be used to differentiate between hepatic and peripheral insulin resistance in patients with HIV lipodystrophy. Furthermore, insulin dynamics, body composition and sex steroid levels will be compared in men and women to determine gender differences in this syndrome. The second aim of this proposal will be to investigate whether the use of an insulin sensitizing agent, metformin, will effectively reduce insulin resistance in HIV-infected patients with the lipodystrophy syndrome. The potential benefits of metformin therapy in the HIV lipodystrophy syndrome are two-fold and include reduction in long-term cardiovascular complications and reversal in the changes in body fat distribution in the HIV lipodystrophy syndrome. In summary, this proposal will investigate the potential pathophysiologic mechanisms of insulin resistance in the HIV lipodystrophy syndrome and will evaluate a novel therapeutic strategy to reverse insulin resistance in patients affected by this syndrome. As HIV patients are living longer, development of successful therapies to prevent potential long-term morbidity associated with insulin resistance is critical for the emerging population of chronically infected, but immunologically stable, population of patients.